Department of Health and Nutritional Sciences, Faculty of Health Sciences, Aichi Gakuin University, 12 Araike, Iwasaki-cho, Nisshin, Aichi, 320-0195, Japan.
Clinical Neurochemistry, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany.
J Neural Transm (Vienna). 2024 Jun;131(6):639-661. doi: 10.1007/s00702-023-02730-6. Epub 2024 Jan 9.
Parkinson's disease is characterized by its distinct pathological features; loss of dopamine neurons in the substantia nigra pars compacta and accumulation of Lewy bodies and Lewy neurites containing modified α-synuclein. Beneficial effects of L-DOPA and dopamine replacement therapy indicate dopamine deficit as one of the main pathogenic factors. Dopamine and its oxidation products are proposed to induce selective vulnerability in dopamine neurons. However, Parkinson's disease is now considered as a generalized disease with dysfunction of several neurotransmitter systems caused by multiple genetic and environmental factors. The pathogenic factors include oxidative stress, mitochondrial dysfunction, α-synuclein accumulation, programmed cell death, impaired proteolytic systems, neuroinflammation, and decline of neurotrophic factors. This paper presents interactions among dopamine, α-synuclein, monoamine oxidase, its inhibitors, and related genes in mitochondria. α-Synuclein inhibits dopamine synthesis and function. Vice versa, dopamine oxidation by monoamine oxidase produces toxic aldehydes, reactive oxygen species, and quinones, which modify α-synuclein, and promote its fibril production and accumulation in mitochondria. Excessive dopamine in experimental models modifies proteins in the mitochondrial electron transport chain and inhibits the function. α-Synuclein and familiar Parkinson's disease-related gene products modify the expression and activity of monoamine oxidase. Type A monoamine oxidase is associated with neuroprotection by an unspecific dose of inhibitors of type B monoamine oxidase, rasagiline and selegiline. Rasagiline and selegiline prevent α-synuclein fibrillization, modulate this toxic collaboration, and exert neuroprotection in experimental studies. Complex interactions between these pathogenic factors play a decisive role in neurodegeneration in PD and should be further defined to develop new therapies for Parkinson's disease.
帕金森病的特征是其独特的病理特征；黑质致密部多巴胺神经元丧失和路易体及含有改性α-突触核蛋白的路易神经突的积累。L-DOPA 和多巴胺替代疗法的有益效果表明多巴胺缺乏是主要致病因素之一。多巴胺及其氧化产物被认为会诱导多巴胺神经元的选择性易损性。然而，帕金森病现在被认为是一种全身性疾病，由多种遗传和环境因素引起的几个神经递质系统功能障碍。致病因素包括氧化应激、线粒体功能障碍、α-突触核蛋白积累、程序性细胞死亡、受损的蛋白水解系统、神经炎症和神经营养因子下降。本文介绍了多巴胺、α-突触核蛋白、单胺氧化酶、其抑制剂和相关基因在线粒体中的相互作用。α-突触核蛋白抑制多巴胺的合成和功能。反之，单胺氧化酶氧化多巴胺会产生有毒的醛、活性氧和醌，这些物质会修饰α-突触核蛋白，促进其在线粒体中的原纤维生成和积累。实验模型中过多的多巴胺会修饰线粒体电子传递链中的蛋白质，并抑制其功能。α-突触核蛋白和常见的帕金森病相关基因产物会改变单胺氧化酶的表达和活性。A型单胺氧化酶与 B 型单胺氧化酶抑制剂（雷沙吉兰和司来吉兰）的非特异性剂量的神经保护有关。雷沙吉兰和司来吉兰可防止α-突触核蛋白纤维化，调节这种毒性协同作用，并在实验研究中发挥神经保护作用。这些致病因素之间的复杂相互作用在 PD 中的神经退行性变中起决定性作用，应进一步明确，以开发新的帕金森病治疗方法。
